Acne vulgaris (“acne”) is a disorder resulting from the action of hormones on the skin's oil glands (sebaceous glands), wherein the sebaceous glands of the skin produce excess sebum, and become enlarged and/or infected when the pore opening becomes plugged with a comedo (a mixture of keratin and sebum). The symptoms of acne include plugged pores and outbreaks of inflamed lesions commonly called pimples.
The pathophysiology of acne vulgaris, the most common cutaneous disease, is the consequence of the interplay of follicular hyperkeratinization, bacteria in the follicular canal, and sebum production. The exact mechanism triggering the development of the comedone and the stimuli causing the non-inflamed lesion to become provoked are poorly understood. The microbiology of acne vulgaris and its immunologic ramifications constitute a major thrust of present research in the elucidation of the pathogenesis of inflammatory acne. Within the microbial flora of the pilosebaceous unit, P. acnes is the most meaningful organism in acne causation.
The methods of acne therapy are usually grouped into several categories such as keratolytics, antibacterials, sebosuppressives, and hormones. Benzoyl peroxide (also referred to as “BP”) is the most widely used topical agent for acne since its introduction in the 1960's. BP is very effective for the treatment of acne because it is antibacterial, functions as a peeling agent, has comedolytic activity, and reduces free fatty acid levels. Concomitant topical treatment of BP and erythromycin is stated to be superior to BP alone. However, no synergistic activity has been found with this combination. Instead, such combination therapies are hypothesized to gain their efficacy by the coupled action of two effective treatments.
Acne lesions usually occur on the face, neck, back, chest, and shoulders. It is the most common skin disease amongst teenagers and young adults. Acne can occur at any age, and is common to all ethnic backgrounds. Nearly 85 percent of people between the ages of 12 and 24 develop this disorder. For most people, acne tends to go away by the time they reach their thirties. However, some people in their forties and fifties continue to have acne, commonly termed “adult acne”.
Several acne treatments are commercially available, such as those in the following categories, for example: topical bactericidals (e.g. triclosan, chlorhexidine gluconate and benzoyl peroxide); topical antibiotics (e.g. erythromycin, tetracycline and clindamycin); oral antibiotics (e.g. tetracyclines and trimethoprim); hormonal treatments (e.g. hormonal contraception in females); topical retinoids (e.g. tretinoin, adapalene and tazarotene); oral retinoids (e.g. isotretinoin, marketed as Accutane®, Roche Pharmaceuticals, N.J.); and phototherapy.
Many of the over-the-counter (“OTC”) acne medications currently marketed rely on chemicals which have an antibacterial and/or a peeling/drying action which aids in breaking down keratin (i.e. keratolytic agent), thus helping to clear plugged pores.
Consequently, there are a wide variety of drugs that are used in topical formulations for the treatment of acne, and there are disadvantages in respect of each drug or combination of drugs. Benzoyl peroxide, resorcinol, salicylic acid, and sulfur are among the most common topical OTC agents used to treat acne. Benzoyl peroxide has an antibacterial effect and also acts as a peeling and drying agent, increasing cell turnover and helping to clear plugged pores.
In general, topical formulations used to treat acne must be water-based, as oil-based formulations can cause or further aggravate acne eruptions.
Benzoyl peroxide is a crystalline solid with a melting point of 103° C. to 106° C., and is insoluble in water.
Benzoyl peroxide is soluble in organic solvents, but most organic solvents are toxic and therefore not suitable for pharmaceutical/cosmetic use. Polar organic solvents such as acetone and ethanol are less toxic, but the flammability of these solvents as well as the ability of these solvents to irritate and strip the skin of its protective mantle limit their use in pharmaceutical or cosmetic compositions.
A common method of treating acne vulgaris is to treat the skin with a benzoyl peroxide dispersion of crystals in a gel/lotion/cream base. However, the use of essentially undissolved benzoyl peroxide crystals has limited efficacy, and consequently requires high concentrations of benzoyl peroxide to be effective. Furthermore, it is difficult for the benzoyl peroxide crystals to penetrate into the comedone and into the sebaceous gland itself, because the comedone plug is a physical barrier and the size of the follicular opening is limited.
One method and formulation which was proposed in U.S. Pat. No. 7,326,420 (“'420 patent”) which is described as increasing the efficacy of peroxides such as benzoyl peroxide in the treatment of skin conditions such as acne relates to methods of increasing radicals formed by peroxides on/in the skin, more specifically near/in the comedone (but not limited thereto), for topical use in dermatology. The methods use the radicals formed by peroxides such as benzoyl peroxide, optimizing conditions such that the skin/comedone is the only place they are formed as opposed to in a storage container or wherever the benzoyl peroxide happens to be from the time of application to when the benzoyl peroxide breaks down into its radicals or is metabolized.
The methods described in the '420 patent may use the principles of photodynamic therapy directed at acne. Instead of forming radicals in cancer cells, the methods form radicals in/by the comedone (skin surface, sebum within P. acnes). The methods use the assumption that radicals derived from BP or other peroxides are the most useful in acne therapy (as opposed to reactive oxygen intermediates used in photodynamic therapy).
In a specific embodiment, the '420 patent relates to the use of transitional metals such as Cu(1) and ferrous ions to increase the efficacy of peroxides such as benzoyl peroxide. It is asserted that such an addition to benzoyl peroxide would increase the generation of benzoyloxyl radicals.
In a further example, U.S. Pat. No. 6,117,843 (“'843 patent”) asserts that it provides novel acne treatment compositions comprising both clindamycin, an antibiotic effective against Propionibacterium acnes, and benzoyl peroxide, a keratolytic and desquamative agent which further possesses a broad antibacterial activity. The two agents are combined in a Pharmaceutically acceptable fluid carrier, usually a gel, which has been found to provide effective topical treatment of acne. The benzoyl peroxide will be present in the carrier at a concentration from 1% by weight to 20% by weight and the clindamycin will be present at a concentration from 0.2% by weight to 4% by weight. By maintaining the compositions at a pH below 7, the tendency of benzoyl peroxide to oxidize and degrade clindamycin is largely overcome and the product remains stable during storage at room temperature for extended periods, typically several months or longer. Additionally, the compositions of the '843 patent are asserted to have been found to remain substantially odor free even after storage at room temperature for extended periods.
Additional instances wherein benzoyl peroxide is employed are described in U.S. Pat. No. 4,497,794, discloses compositions combining erythromycin and benzoyl peroxide for the treatment of acne, as described above. Other patents disclosing the combination of erythromycin and benzoyl peroxide for acne treatment and other purposes include U.S. Pat. No. 4,411,893; U.S. Pat. No. 4,692,329; and British Patent No. 1,594,314. The combination of erythromycin with other organic peroxides for the treatment of acne is described in British Patent No. 2,088,717. Other formulations containing benzoyl peroxide for the treatment of acne are described in U.S. Pat. Nos. 3,535,422, 4,056,611; 4,318,907; 4,923,900; 4,387,107; and 4,228,163. Other peroxide formulations for treating acne are described in U.S. Pat. No. 4,607,101. The use of clindamycin and other lincomycin antibiotics for the treatment of acne is described in U.S. Pat. No. 3,969,516. Hirschmann (1988) Arch. Dermatol. 124:1691-1700 and Fulton, Jr., et al. (1974) Arch. Dermatol. 110:83-86 describe the topical use of antibiotics for the treatment of acne.
Consequently, commercially available topical formulations of benzoyl peroxide have several disadvantages, since they: (1) have a limited ability to penetrate the skin and consequently have low efficacy for the dose administered; (2) cannot be formulated as clear compositions and sprays; and (3) leave an aesthetically undesirable white, powder residue on the skin once the topical formulation dries.
Relatively little progress has been made in reaching the target of safe and effective non-invasive transdermal delivery of formulations for macromolecules, including peptides and proteins. Barriers to developing transdermal formulations for proteins, peptides and other large and small molecules include poor intrinsic permeability, cellular enzymatic degradation and chemical instability. Pharmaceutical approaches to address these barriers that have been successful with traditional small, organic drug molecules have not readily translated into effective peptide and protein formulations. The ability of molecules to permeate the skin effectively appears to be related to molecular size, lipid solubility and peptide protein ionization. Molecules less than 1000 daltons appear to cross the skin barriers rapidly. As molecular size increases, the permeability of the molecule decreases rapidly. Lipid soluble compounds are more permeable than non-lipid soluble molecules. Maximum absorption occurs when molecules are un-ionized or neutral in electrical charges. Charged molecules, therefore, present the biggest challenges to absorption through the skin.
Some enhancers, especially those related to bile salts, and some protein solubilizing agents are extremely potent in transporting the molecules effectively across the tight junctions and skin. Several approaches have been utilized to improve the transport of the bile salt-based delivery systems, including the use of protease inhibitors and various polymer matrices. Other attempts to deliver large molecules using single bile acids or enhancing agents in combination with protease inhibitors and biodegradable polymeric materials similarly failed to achieve therapeutic levels of proteinic drugs in the patient. Single enhancing agents fail to loosen tight cellular junctions for the time needed to permit passage of large molecules through the skin membranes without further degradation.
Various transmission systems have been proposed in connection with the delivery of small molecules such as local anesthetic compounds. U.S. Pat. No. 5,013,545 to Blackmon et. al. discloses aqueous gel-containing topical medications comprising high concentrations of alcohol, water and topically effective amounts of a pharmaceutical active such as hydrocortisone, diphenhydramine hydrochloride, lidocaine or miconazole nitrate in a gel matrix primarily consisting of water-soluble carboxyvinyl polymers. A gel clarifying agent may be optionally added for aesthetic reasons.
U.S. Pat. No. 4,937,078 to Mezie et. al. discloses the incorporation of certain concentrations of topical anesthetic actives into liposomes which are of a substantially greater size than nano particles. U.S. Pat. No. 5,081,158 to Pomerantz discloses the use of medicated protective films as a carrier for topical anesthetics. The films are comprised of hydroxypropyl cellulose (HPC) and an esterification agent which renders the HPC soluble in a non-volatile solvent such as ethanol, isopropanol or methanol. Medicinal compounds such as benzocaine and a variety of other topical anesthetics, antibiotics and steroids are incorporated which, when applied to the skin, result in situ formed medicated films from which the actives are released to provide a sustained supply of the medicine at the treatment site.
U.S. Pat. No. 5,002,974 to Geria discloses a topical anesthetic and skin moisturizing composition comprising any one of a number of topical anesthetics, including pramoxine, in an oil-in-water emulsion including a dissolved surface active agent. The composition is asserted to provide an aesthetically pleasing analgesic skin care product. The emulsion not only provides relief from the pain associated with irritated skin but is asserted to soften and moisturize the skin with an oily coating. U.S. Pat. No. 4,493,591 to Fourman et al discloses skin care cosmetic formulations comprised of a cellulosic polymer/solvent system capable of dispersing thin, substantive films upon the skin. Such films may serve as a carrier for sun blocking agents and insect repellents and also serve to prevent water loss form the skin surface to the environment.
Finally, U.S. Pat. No. 4,389,418 to Burton et. al., in a more general and traditional sense, discloses the use of hydrocarbons such as petrolatum, paraffin wax and ozokerite and other emollients as skin moisturizing materials. These function by covering the skin with a hydrophobic occlusive film which prevents water loss from the skin to the environment.